A randomized, open-label, phase III trial of NOV-002 in combination with paclitaxel (P) and carboplatin (C) versus paclitaxel and carboplatin alone for the treatment of advanced non-small cell lung cancer (NSCLC).

Abstract

LBA7007 Background: NOV-002 is a formulation of disodium glutathione disulfide (GSSG). GSSG is a naturally occurring substance that functions as a component of the glutathione (GSH) pathway, vital to the regulation of the intracellular redox state. A key function of the GSH/GSSG redox couple is to dynamically regulate protein functions, including cell signaling pathways, through the reversible formation of mixed disulfides between protein cysteines and GSH (S-glutathionylation). Based on positive results from a randomized, phase I/II study of carboplatin and paclitaxel (CP) with or without NOV-002, as well as positive results from 2 ex-U.S. phase II studies with cisplatin-based chemotherapy, an international phase III randomized trial was launched. Methods: Patients with advanced NSCLC (stages wet IIIB and IV, inclusive of all histological subtypes) were eligible if they had a PS of 0-1 and adequate end-organ function. Patients with CNS metastases were excluded. Eligible patients were randomized to C (AUC 6), P (200 mg/m2), and NOV-002 (Group A) or C and P alone (Group B). NOV-002 was administered as two-60 mg IV boluses on day -1 of cycle 1 and as one IV bolus on day 1 of each cycle, followed by daily 60-mg subcutaneous injections. A total of 725 events were required to detect a difference in overall survival (OS) from 10.0 to 12.5 months with 85% power and a two-sided significance level of 0.05. No interim analysis was performed. Results: From 11/06 until 9/09, 903 patients were randomized, with target enrollment reached in March 2008. Patient characteristics for Groups A and B were as follows: stage IV (91.5/90.8%), PS 1 (76.6/72.6%), male (69.9/72.4%), never smoker (22.3/19.1%) median age (59.6/59.5), and histology (adenocarcinoma [40.0/36.8%] squamous [41.2/40.8%]). The median overall survival for Groups A and B was 10.2/10.8 months (p = 0.375), median progression-free survival was 5.3/5.6 months, objective response rate was 26.6/26.0% and 54/53% of patients completed at least six cycles of chemotherapy. Major toxicities for Groups A and B included grade 3/4 neutropenia (29.7/26.3%), febrile neutropenia (2.2/1.8%), grade 3/4 thrombocytopenia (3.8/2.9%), and grade 3/4 neuropathy (2.9/2.4%). Adverse events resulting in death in Groups A and B were reported in 5.6 and 3.1%, respectively. Conclusions: The addition of NOV-002 to CP does not improve overall survival in patients with advanced NSCLC. NOV002 does not appear to add to the overall toxicity of chemotherapy. [Table: see text]